Quinoline-based thiazolyl-hydrazones target cancer cells through autophagy inhibition

Heterocyclic pharmacophores such as thiazole and quinoline rings have a significant role in medicinal chemistry. They are considered privileged structures since they constitute several Food and Drug Administration (FDA)-approved drugs for cancer treatment. Herein, we report the synthesis, in silico evaluation of the ADMET profiles, and in vitro investigation of the anticancer activity of a series of novel thiazolyl-hydrazones based on the 8-quinoline (1a-c), 2-quinoline (2a-c), and 8-hydroxy-2-quinolyl moiety (3a-c). The panel of several human cancer cell lines and the nontumorigenic human embryonic kidney cell line HEK-293 were used to evaluate the compound-mediated in vitro anticancer activities, leading to [2-(2-(quinolyl-8-ol-2-ylmethylene)hydrazinyl)]-4-(4-methoxyphenyl)-1,3-thiazole (3c) as the most promising compound. The study revealed that 3c blocks the cell-cycle progression of a human colon cancer cell line (HCT-116) in the S phase and induces DNA double-strand breaks. Also, our findings demonstrate that 3c accumulates in lysosomes, ultimately leading to the cell death of the hepatocellular carcinoma cell line (Hep-G2) and HCT-116 cells, by the mechanism of autophagy inhibition. A series of quinoline-based thiazolyl-hydrazones was synthesized and evaluated for antiproliferative activity. The most promising compound, 2-(2-(quinolyl-8-ol-2-ylmethylene)hydrazinyl)-4-(4-methoxyphenyl)-1,3-thiazole (3c), accumulates in lysosomes, halts cell-cycle progression at the S phase and induces DNA double-strand breaks, indicating the importance of the 2-hydroxy-8-hydroxyquinoline fragment for targeting cancer cells via autophagy inhibition.image